The present invention describes novel nitrosated and/or nitrosylated H2 receptor antagonist compounds, and novel compositions comprising at least one H2 receptor antagonist compound that is optionally substituted with at least one NO and/or NO2 group, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase. The present invention also provides methods for treating and/or preventing gastrointestinal disorders; improving gastroprotective properties of H2 receptor antagonists; decreasing the recurrence of ulcers; facilitating ulcer healing; treating and/or preventing inflammations and microbial infections, ophthalmic diseases and disorders, multiple sclerosis, and viral infections; and decreasing or reducing the gastrointestinal toxicity associated with the use of nonsteroidal antiinflammatory compounds.
H2 receptor antagonists are a well known class of drugs used in the management of gastrointestinal disorders. H2 antagonists competitively inhibit the interaction of histamine with H2 receptors. Although H2 receptors are present in numerous tissues, including vascular and bronchial smooth muscle, they appear to have a minimal role in modulating physiological functions other than gastric secretion.
H2 receptor antagonists inhibit gastric acid secretion elicited by histamine and other H2 receptor agonists in a dose-dependent, competitive manner. The H2 receptor antagonists also inhibit acid secretion elicited by gastrin and, to a lesser extent, by muscarinic agonists. H2 receptor antagonists inhibit basal (fasting) and nocturnal acid secretion and that stimulated by food, sham feeding, fundic distention, and various pharmacological agents. The H2 receptor antagonists reduce both the volume of gastric juice secreted and its hydrogen ion (H+) concentration. Despite their good antisecretory properties, H2 receptor antagonists are not unanimously recognized as gastroprotective agents. In addition, there is a high relapse rate associated with treating gastrointestinal disorders with H2 receptor antagonists as they do not eliminate Helicobacter pylori (Campylobacter pylori), the bacteria responsible for peptic ulcer disease, gastric lymphoma and adenocarcinoma.
A variety of adverse reactions have been ascribed to H2 receptor antagonists, such as cimetidine and ranitidine, reflecting, in part, the very large number of patients who have been treated with these drugs. The incidence of adverse reactions is low, and the adverse reactions are generally minor. The low incidence is attributable in part to the limited function of H2 receptors in organs other than the stomach and to the poor penetration of these agents across the blood-brain barrier.
The most common side effects of H2 receptor antagonists, such as cimetidine, are headache, dizziness, nausea, myalgia, skin rashes, and itching. The incidence of symptoms related to the central nervous system (CNS) appears to be higher in the elderly and in patients with impaired renal function. Loss of libido, impotence and gynecomastia are sometimes observed in patients who receive long-term therapy with high doses of H2 receptor antagonists, such as cimetidine.
Sorba et al, Arzneim-Forsch Drug Res., 47(II):849-854 (1997), the disclosure of which is incorporated by reference herein in its entirety, have developed a drug that combines a H2 receptor antagonist with a nitric oxide (NO)-donor furoxan moiety. This drug is reported to retain weaker H2 receptor antagonist activity relative to the parent drug but shows a NO-dependent gastroprotective effect.
U.S. Pat. No. 5,403,830, the disclosure of which is incorporated by reference herein in its entirety, describes pharmaceutical compositions and methods of treating gastrointestinal disorders by administering bismuth-containing agents in conjunction with a H2 receptor antagonist. U.S. Pat. Nos. 5,403,830, and 5,407,688, and Ivnov et al, J. Pharm. Pharmacol., 48:297-301 (1996) and Marazova et al, J. Pharm. Pharmacol., 49:791-795 (1997), the disclosures of each of which are incorporated by reference herein in their entirety, describe treating or preventing gastrointestinal disorders by administering bismuth containing agents. U.S. Pat. Nos. 4,705,683, 4,900,741, 5,112,850 and 5,656,652, the disclosures of which are incorporated by reference herein in their entirety, describe administering H2 receptor antagonists with polyacrylates, antimuscarinic agents, trapencine and antacids, respectively. U.S. Pat. No. 5,656,652, the disclosure of which is incorporated by reference herein in its entirety, describes the use of H2 antagonists and antacids for the treatment of gastrointestinal disorders.
The administration of NSAIDs, such as indomethacin or ibuprofen, with H2 receptor antagonists, such as cimetidine, is described in U.S. Pat. Nos. 5,037,815 and 4,279,906 and in WO 94/07541, the disclosure of each of which is incorporated by reference herein in its entirety. U.S. Pat. Nos. 5,102,902, 5,541,212 and 5,578,597, the disclosures of each of which are incorporated by reference herein in their entirety, disclose the use of H2 receptor antagonists for treating multiple sclerosis and retrovirus infections.
There is a need in the art for H2 receptor antagonist compounds that have gastroprotective properties, decrease the recurrence of ulcers, facilitate ulcer healing and that can be used at low dosages. The present invention is directed to these, as well as other, important ends.
The present invention provides compounds comprising a H2 receptor antagonist to which is linked at least one NO and/or NO2 group (i.e., nitrosylated and/or nitrosated). The H2 receptor antagonists can be, for example, histamine analogs that contain a bulky side chain instead of an ethylamine moiety and retain the imidazole ring of histidine, such as cimetidine. The imidazole ring can be replaced by a furan (e.g., rantidine) or a thiazole (e.g., famotidine, nizatidine). The H2 receptor antagonists can also be, for example, amide derivatives, such as, for example, roxatidine or a guanidino derivative, such as, for example, ebrotidine or famotidine. The present invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier.
Another aspect of the invention provides compositions comprising at least one H2 receptor antagonist, that is optionally substituted with at least one NO and/or NO2 group (i.e., nitrosylated and/or nitrosated), and at least one compound that donates, transfers or releases nitric oxide and/or stimulates endogenous production of nitric oxide (NO) or endothelium-derived relaxing factor (EDRF) in vivo and/or is a substrate for nitric oxide synthase.
Yet another aspect of the present invention provides methods for treating gastrointestinal disorders, improving the gastroprotective properties of H2 receptor antagonists, increasing the rate of ulcer healing, decreasing the rate of recurrence of ulcers, treating inflammations, treating ophthalmic diseases and disorders, and treating microbial infections in a patient in need thereof which comprises administering to the patient at least one H2 receptor antagonist compound, that is optionally substituted with at least one NO and/or NO2 group (i.e., nitrosylated and/or nitrosated), and, optionally, at least one compound that donates, transfers or releases nitric oxide and/or stimulates endogenous production of NO or EDRF in vivo and/or is a substrate for nitric oxide synthase. The H2 receptor antagonist that is optionally linked to at least one NO and/or NO2 group and nitric oxide donor can be administered separately or as components of the same composition.
The present inventions also describes methods to decrease or reverse gastrointestinal toxicity and facilitate ulcer healing resulting from the administration of nonsteroidal antiinflammatory drugs (NSAIDs); methods to improve the gastroprotective properties, anti-Helicobacter properties and antacid properties of H2 receptor antagonists; methods for preventing or treating gastrointestinal disorders; methods for treating multiple sclerosis; methods for treating ophthalmic diseases and disorders; and methods for treating viral infections, such as HIV disease. The nitrosated and/or nitrosylated NSAID and nitric oxide donor can be administered separately or as components of the same composition. These and other aspects of the present invention are explained in detail herein.